Identification of differentially expressed genes profiles in a combined mouse model of Parkinsonism and colitis

Abstract

Different cellular mechanisms have been described as being potentially involved in the progression of neurodegeneration in Parkinson's disease, although their role is still unclear. The present study aimed to identify in detail, through differentially expressed genes analysis by bioinformatics approaches, the molecular mechanisms triggered after a systemic insult in parkinsonian mice. To address this objective, we combined a dextran sodium sulfate (DSS)-induced ulcerative colitis experimental mice model with an acute 1-methyl-4-phenyl-1,2,3,6-tetradropyridine (MPTP) intoxication. The animals were divided into four experimental groups based on the different treatments: (i) control, (ii) DSS, (iii) MPTP and (iv) MPTP + DSS. The data obtained by microarray and functional enrichment analysis point out the implication of different molecular mechanisms depending on the experimental condition. We see, in the striatum of animals intoxicated only with DSS, dysfunction processes related to the blood. On the other hand, oxidative stress processes are more prominent at the MPTP intoxicated mice. Finally, differentially expressed genes within the MPTP + DSS show functional enrichment in inflammation and programmed cell death. Interestingly, we identify a significant synergistic negative effect of both toxins since the expression of differentially expressed genes (DEGs) related to balanced cellular homeostasis was not enough to prevent processes associated with cell death. This work provides detailed insights into the involvement of systemic inflammation, triggered after an insult in the colon, in the progression of the degeneration in Parkinsonism. In this way, we will be able to identify promising therapeutic targets that prevent the contribution of inflammatory processes in the progression of Parkinson's disease. Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder following Alzheimer's disease. The main pathological feature of PD is the progressive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc), with the subsequent loss of dopamine (DA) in the striatum. Although much uncertainty still exists about the aetiology of PD, available evidence suggests the implication of numerous processes such as oxidative stress, mitochondrial dysfunction, inflammation and cell apoptosis. Specifically, the deleterious role of systemic inflammation in the onset and progression of PD is becoming evident, so that the interest in its study has increased in the last years 1. In this sense, it is showed that dopaminergic neurons are more vulnerable to oxidative stress and pro-inflammatory cytokines because of their low levels of intracellular glutathione concentrations 2. Thus, a sustained systemic or brain inflammation involves activated microglia cells that secrete pro-inflammatory factors that damage neurons 3. At the same time, damaged neurons release toxic factors that recruit more glial cells, resulting in a fatal vicious cycle.

Intestinal Inflammation and Parkinson’s Disease

“…A study showed that acute DSS-induced colitis enhanced infiltration of the hippocampus with periphery immune cells, along with increased pro-inflammatory cytokines and inflammatory M1-like microglia [ 146 ]. A recent gene analysis study has provided insights into the involvement of systemic inflammation after colon injury, which is related to the degeneration process of PD [ 147 ]. Scientists combined a DSS-induced UC experimental mice model with an acute 1-methyl-4-phenyl-1,2,3,6-tetradropyridine (MPTP) intoxication.…”

Inflammation and regulatory T cell genes are differentially expressed in peripheral blood mononuclear cells of Parkinson’s disease patients

“…Tumor necrosis factor (TNF) signaling pathway was also found to be a key pathway involved in PD pathogenesis 19 . Analyses of differentially expressed gene profiles in experimental mouse model of MPTP induced PD revealed increased expression of systemic inflammation and programmed cell death genes 20 Zhang et al reported decreased expression of complex I transcripts and increased expression of heat shock proteins and some anti-apoptotic gene groups in PD patients 21 . Durrenberger et al showed upregulation of P2X7 and NOS pathways thereby emphasizing that extracellular ATP and reactive astrocytes are responsible of microglial activation and subsequent release of proinflammatory cytokines that contribute to dopaminergic cell death 22 .…”

Intragastric administration of low-dose rotenone post-colitis exacerbates damage to the nigrostriatal dopaminergic system in Parkinson’s disease: The pace accelerates even more

“…In this line, Martínez et al were the first to check the effect of acute colonic inflammation induced by DSS pre-treatment on MPTP induced Parkinsonism mouse model. Their findings demonstrated that DSS-induced injury circumscribed to the colon exacerbates DAergic neurodegeneration and glial response in the nigrostriatal pathway 83 . Our immunofluorescence experiment results supported previous research and showed co-localization of α-syn in TH + neurons of SNpc in rotenone treated pre colitic mice compared to the control group.…”